Ecdysteroid-Containing Squalenoylated Self-Assembling Nanoparticles Exert Tumor-Selective Sensitization to Reactive...

Central nervous system (CNS) tumors are exceptionally difficult to treat, and oxidative stress-inducing radiotherapy is an important treatment modality. In this study, we examined self-assembling pro-drug nanoconjugates of naturally derived antitumor ecdysteroids, which were designed to interfere with oxidative stress in brain tumor cells. Eight ecdysteroid-squalene conjugates were semi-synthesized and formulated into self-assembled aqueous nanosuspensions, which showed excellent stability for up to 16 weeks. The nanoassemblies demonstrated a strong dose-dependent sensitizing effect to tert-butyl hydroperoxide (tBHP)-induced oxidative damage in SH-SY5Y cells, while exerting a strong protective effect in MRC-5 fibroblast cells. In contrast, free ecdysteroids protected both cell lines from tBHP-induced damage. This suggests an important role for squalenoylation in the antitumor effect and indicates that our conjugates have potential as highly selective adjuvants in radiotherapy by sensitizing cancer cells and protecting surrounding tissues. Furthermore, our findings suggest a potential neuroprotective effect of nonconjugated ecdysteroids.